Gaucher Disease

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Gaucher disease is an autosomal recessive lysosomal storage disorder caused by glucocerebrosidase deficiency, leading to glucocerebroside accumulation in macrophages (Gaucher cells with "crinkled tissue paper" cytoplasm). Type 1 (non-neuronopathic) accounts for 95% of cases and is most common in Ashkenazi Jewish populations (1:800 prevalence). Key orthopaedic manifestations include bone crises (severe pain and fever mimicking osteomyelitis but culture-negative—do NOT treat with antibiotics), AVN of the hip and shoulder, pathological fractures, and Erlenmeyer flask deformity (failure of distal femur metaphyseal remodeling). Enzyme replacement therapy (ERT) with imiglucerase has transformed outcomes and is first-line treatment.

Gaucher Disease is the most common lysosomal storage disorder.

Prevalence:

• General population: 1 in 40,000-60,000
• Ashkenazi Jewish population: 1 in 800 (carrier frequency 1:15)
• Most common lysosomal storage disorder

Genetics:

• Autosomal recessive inheritance
• GBA gene mutation (chromosome 1)
• Encodes glucocerebrosidase (beta-glucosidase)
• Over 400 mutations identified
• Common mutations: N370S (Type 1), L444P (more severe)

Pathophysiology:

• Glucocerebrosidase deficiency
• Glucocerebroside (glucosylceramide) accumulates
• Accumulates in macrophages → Gaucher cells
• Gaucher cells infiltrate bone marrow, spleen, liver

Gaucher Cells:

• Macrophages engorged with glucocerebroside
• "Crinkled tissue paper" or "wrinkled silk" cytoplasm
• Found in bone marrow, spleen, liver, lymph nodes
• Histiocytes 20-100 microns in diameter

Mechanism of Bone Disease:

1. Marrow Infiltration

   • Gaucher cells replace normal marrow
   • Decreased hematopoiesis → cytopenias
   • Marrow expansion → cortical thinning

2. Vascular Compromise

   • Marrow infiltration → ischemia
   • Bone infarcts and bone crises
   • AVN of femoral head, humeral head

3. Bone Remodeling Failure

   • Interference with osteoclast/osteoblast function
   • Failed metaphyseal remodeling → Erlenmeyer flask
   • Osteopenia and pathological fractures

Type 1 (Non-neuronopathic):

• 95% of Gaucher patients
• No primary neurological involvement
• Variable severity - some diagnosed in adulthood
• Significant bone disease
• Excellent response to ERT

Type 2 (Acute neuronopathic):

• Presentation in infancy (under 2 years)
• Severe neurological deterioration
• Brainstem dysfunction, seizures
• Death usually by 2-3 years
• ERT does not cross blood-brain barrier

Type 3 (Chronic neuronopathic):

• Childhood presentation
• Slower neurological progression than Type 2
• Bone and visceral disease similar to Type 1
• ERT helps visceral disease, not neurological

Bone Crises (Acute):

• Severe bone pain, often femur or tibia
• Fever, malaise
• Elevated ESR, CRP
• Mimics osteomyelitis - critical differential
• Caused by acute marrow ischemia/infarction
• May last days to weeks
• Treatment: analgesia, hydration, steroids

Avascular Necrosis:

• Femoral head most common (40% of Type 1)
• Humeral head also affected
• Chronic marrow infiltration → vascular compromise
• May progress despite ERT if established
• Often requires arthroplasty

Erlenmeyer Flask Deformity:

• Failure of metaphyseal remodeling
• Classic at distal femur
• Wide metaphysis, narrow diaphysis
• "Flask" shape on X-ray
• Bilateral and symmetric
• Does not cause symptoms directly

Pathological Fractures:

• Osteopenia from marrow expansion
• Cortical thinning
• Vertebral compression fractures
• Long bone fractures (often minimal trauma)
• Healing may be delayed

Other Bone Features:

• Bone infarcts (medullary)
• Osteonecrosis of vertebrae
• Growth retardation in children
• Chronic bone pain

Hematological:

• Anemia (Gaucher cell marrow replacement)
• Thrombocytopenia (splenic sequestration)
• Bleeding tendency (both platelet and coagulation defects)
• Leukopenia (less common)

Hepatosplenomegaly:

• Massive splenomegaly (25x normal)
• Hepatomegaly (2-3x normal)
• Hypersplenism → cytopenias
• May cause abdominal discomfort

Other:

• Growth retardation
• Delayed puberty
• Pulmonary involvement (rare)
• Increased malignancy risk (myeloma, lymphoma)

Definitive Diagnosis:

• Glucocerebrosidase enzyme activity (leukocytes or fibroblasts)
  • Under 15% of normal is diagnostic
• Genetic testing - GBA gene mutations
  • Confirms diagnosis
  • Allows family screening

Laboratory:

• Chitotriosidase: Markedly elevated (biomarker)
• Acid phosphatase: Elevated
• Ferritin: Elevated
• CBC: Anemia, thrombocytopenia
• Coagulation: May be abnormal

Imaging:

• Plain X-rays: Erlenmeyer flask, osteopenia, lytic lesions
• MRI: Gold standard for bone assessment
  • T1: Low signal (fatty marrow replacement)
  • Bone marrow burden score
  • AVN detection
  • Bone infarcts
• CT: Hepatosplenomegaly assessment
• DXA: Bone mineral density

MRI Bone Marrow Burden Score:

• Quantifies severity of marrow infiltration
• Used to monitor treatment response
• Correlates with risk of bone complications

Severity Scoring:

Interpretation:

• Used to guide treatment intensity
• Monitor response to ERT
• Predict fracture risk

AVN Management:

1. Early AVN (Pre-collapse):

   • Core decompression
   • Limited evidence in Gaucher-related AVN
   • May slow progression
   • Coordinate with hematology

2. Advanced AVN (Collapse/Arthritis):

   • Total hip arthroplasty
   • Total shoulder arthroplasty
   • Higher complication rate than primary OA
   • Increased bleeding risk

THA Considerations:

• Platelet transfusion may be needed (target greater than 50,000)
• Cement may be preferable (poor bone quality)
• Extended prophylaxis (increased VTE risk)
• Consider tranexamic acid
• Liaise with hematology pre-operatively

Pathological Fractures:

• Surgical fixation when indicated
• Delayed healing expected
• May require bone grafting
• Internal fixation may be challenging (soft bone)

Splenectomy:

• Rarely needed with ERT
• May worsen bone disease (increased bone marrow infiltration)
• Only for massive, symptomatic splenomegaly
• Partial splenectomy preferred

Skeletal:

• Progressive AVN requiring arthroplasty
• Chronic bone pain
• Multiple pathological fractures
• Vertebral collapse
• Growth retardation

Hematological:

• Severe anemia requiring transfusion
• Bleeding complications
• Hypersplenism

Other:

• Pulmonary hypertension
• Increased malignancy risk (myeloma)
• Parkinsonism (GBA heterozygotes)

Specific to Gaucher:

• Increased bleeding (platelet and coagulation defects)
• Delayed bone healing
• Higher infection risk
• Implant loosening (poor bone quality)
• Prolonged recovery

Prevention:

• Pre-operative hematology consultation
• Platelet transfusion if needed
• Optimize ERT dosing
• Meticulous hemostasis
• Consider cement fixation

ERT Era Outcomes:

• Life expectancy near-normal for Type 1
• Dramatic reduction in splenectomy rates
• Prevention of new bone complications
• Quality of life greatly improved

Bone Disease Outcomes:

• Established AVN often progresses despite ERT
• New bone crises reduced on ERT
• Bone density improves slowly
• Pathological fractures less common with treatment

Arthroplasty Outcomes:

• Good functional results
• Higher complication rate than primary OA
• May need earlier revision
• Coordinate perioperative care with hematology

PBS Status:

• ERT (imiglucerase, velaglucerase) on PBS for confirmed Gaucher disease
• Eliglustat on PBS for Type 1 (CYP2D6 testing required)
• Specialist prescription required
• Life Sciences Orphan Drugs Program

Australian Gaucher Network:

• Specialized clinics in major tertiary centers
• Multidisciplinary care model
• Patient support and advocacy

Referral Pathways:

• Hematology/metabolic specialist for diagnosis and ERT
• Orthopaedics for bone complications
• Pre-operative optimization essential

Epidemiology: Gaucher disease is rare in Australia, with approximately 100-150 diagnosed patients nationally. Higher prevalence in Ashkenazi Jewish communities. Cases managed through specialist metabolic disease centres in major tertiary hospitals.

Enzyme Replacement Therapy: Imiglucerase and velaglucerase are available through the Life Saving Drugs Program (LSDP) for eligible patients with Type 1 Gaucher disease. Access requires application through specialist metabolic physicians.

Orthopaedic Considerations: Patients requiring joint replacement or spinal surgery should be managed in collaboration with haematology and metabolic medicine. Close monitoring of platelet counts and bleeding risk is essential perioperatively.

Multidisciplinary Care: Comprehensive care available at specialist centres including Royal Children's Hospital Melbourne, Westmead Children's Hospital Sydney, and adult metabolic services at major teaching hospitals.